Nitric Oxide/Reactive Oxygen Species Generation and Nitroso/Redox Imbalance in Heart Failure: From Molecular Mechanisms to Therapeutic Implications

Adaptation of the heart to intrinsic and external stress involves complex modifications at the molecular and cellular levels that lead to tissue remodeling, functional and metabolic alterations, and finally to failure depending upon the nature, intensity, and chronicity of the stress. Reactive oxygen species (ROS) have long been considered as merely harmful entities, but their role as second messengers has gradually emerged. At the same time, our comprehension of the multifaceted role of nitric oxide (NO) and the related reactive nitrogen species (RNS) has been upgraded. The tight interlay between ROS and RNS suggests that their imbalance may implicate the impairment in physiological NO/redox-based signaling that contributes to the failing of the cardiovascular system. This review initially provides basic concepts on the role of nitroso/oxidative stress in the pathophysiology of heart failure with a particular focus on sources of ROS/RNS, their downstream targets, and endogenous modulators. Then, the role of NO/redox regulation of cardiomyocyte function, including calcium homeostasis, electrogenesis, and insulin signaling pathways, is described. Finally, an overview of old and emerging therapeutic opportunities in heart failure is presented, focusing on modulation of NO/redox mechanisms and discussing benefits and limitations. Antioxid. Redox Signal. 14, 289–331. Introduction Evidence for a Role of ROS in HF: From Acute Stressor to Signaling Pathways Sources and species of ROS Mitochondria NADPH oxidases Xanthine oxidase NO and RNS in HF Signals activating ROS production Downstream effectors and targets Endogenous Modulators of ROS Signals Antioxidant enzymatic system Cytosolic and mitochondrial SOD Catalase Glutathione peroxidase Antioxidant enzymatic defense in HF Differences Between RV and LV in HF ROS/RNS and Functional Remodeling in Failing Cardiomyocyte: Focus on Excitation–Contraction Coupling and Arrhythmogenesis NO/ROS and calcium homeostasis ROS and the arrhythmogenic hazard in HF Cardiomyocyte Energy Sources in the Healthy and in the Failing Heart Energy substrate metabolism: the cytoplasmic branch Energy substrate metabolism: the mitochondrial branch Insulin resistance impacts glucose and fatty acid metabolism Therapeutic Opportunities for HF The pharmacological management of HF includes indirect antioxidants Angiotensin-converting enzyme inhibitors Angiotensin type 1 receptor antagonists: losartan β-blockers: waiting for the third generation Nitrates: better not just alone but hybrid nitrates Metabolically active antioxidants: from a failure new successes? Inhibitors of fatty acid oxidation: beyond etomoxir Incretin mimetics Metformin Statins: lights and shadows Tetrahydrobiopterin Conclusions